Ablation of ERO1A induces lethal endoplasmic reticulum stress responses and immunogenic cell death to activate anti-tumor immunity

Immunophenotyping of the tumor microenvironment (TME) is essential for enhancing immunotherapy efficacy. However, strategies characterizing TME exhibit significant heterogeneity. Here, we show that endoplasmic reticular oxidoreductase-1α (ERO1A) mediates an immune-suppressive and attenuates response to PD-1 blockade. Ablation ERO1A in cells substantially incites anti-tumor T cell immunity promotes efficacy aPD-1 therapeutic models. Single-cell RNA-sequencing analyses confirm correlates with immunosuppression dysfunction CD8+ along anti-PD-1 treatment. In human lung cancer, high expression associated a higher risk recurrence following neoadjuvant immunotherapy. Mechanistically, ablation impairs balance between IRE1α PERK signaling activities induces lethal unfolded protein responses undergoing reticulum stress, thereby via immunogenic death. These findings reveal how immunosuppression, highlighting its potential as target cancer